Contrasting philosophical and scientific views in the long history of studying the generation of form in development.

Focusing on the opposing ways of thinking of philosophers and scientists to explain the generation of form in biological development, I show that today's controversies over explanations of early development bear fundamental similarities to the dichotomy of preformation theory versus epigenesis in Greek antiquity. They are related to the acceptance or rejection of the idea of a physical form of what today would be called information for the generating of the embryo as a necessary pre-requisite for specific development and heredity. As a recent example, I scrutinize the dichotomy of genomic causality versus self-organization in 20th and 21st century theories of the generation of form. On the one hand, the generation of patterns and form, as well as the constant outcome in development, are proposed to be causally related to something that is "preformed" in the germ cells, the nucleus of germ cells, or the genome. On the other hand, it is proposed that there is no pre-existing form or information, and development is seen as a process where genuinely new characters emerge from formless matter, either by immaterial "forces of life," or by physical-chemical processes of self-organization. I also argue that these different ways of thinking and the research practices associated with them are not equivalent, and maintain that it is impossible to explain the generation of form and constant outcome of development without the assumption of the transmission of pre-existing information in the form of DNA sequences in the genome. Only in this framework of "preformed" information can "epigenesis" in the form of physical and chemical processes of self-organization play an important role.

Self-Organization and Genomic Causality in Models of Morphogenesis.

The debate about what causes the generation of form and structure in embryological development goes back to antiquity. Most recently, it has focused on the divergent views as to whether the generation of patterns and form in development is a largely self-organized process or is mainly determined by the genome, in particular, complex developmental gene regulatory processes. This paper presents and analyzes pertinent models of pattern formation and form generation in a developing organism in the past and the present, with a special emphasis on Alan Turing's 1952 reaction-diffusion model. I first draw attention to the fact that Turing's paper remained, at first, without a noticeable impact on the community of biologists because purely physical-chemical models were unable to explain embryological development and often also simple repetitive patterns. I then show that from the year 2000 and onwards, Turing's 1952 paper was increasingly cited also by biologists. The model was updated to include gene products and now seemed able to account for the generation of biological patterns, though discrepancies between models and biological reality remained. I then point out Eric Davidson's successful theory of early embryogenesis based on gene-regulatory network analysis and its mathematical modeling that not only was able to provide a mechanistic and causal explanation for gene regulatory events controlling developmental cell fate specification but, unlike reaction-diffusion models, also addressed the effects of evolution and organisms' longstanding developmental and species stability. The paper concludes with an outlook on further developments of the gene regulatory network model.

The idea of constancy in development and evolution - Scientific and philosophical perspectives.

The ability of developmental systems to produce constant phenotypes, even in a wide range of different environments, and the longstanding stability of species are among the most remarkable phenomena in biology. I argue that understanding the longstanding constancy and stability of species or the constant outcome of development in different environments are also prerequisites for explaining stable change (i.e., change that does not consist of random plasticity). Various approaches to account for stable changes in development are based on the causal role of genes and an organized genome, mathematical-physical-chemical models, or a combination of both. I argue that the constancy of developmental outcome and the longstanding stability of species are associated with organisms' structural and organizational hierarchies, particularly highly organized gene-regulatory networks and genetic causality, which are fundamental principles of life. Mathematical-physical-chemical models that marginalize these principles cannot convincingly account for the observed constancy in development and evolution. However, an integration of physical-chemical processes such as reaction-diffusion mechanisms and genome-based mechanisms of form generation has recently proved fruitful in explaining the development of some periodic structures. Constancy and change were also major topoi in ancient Greek philosophy, in which prominent philosophical schools such as the atomists attempted to bridge the antinomy between them by basing stable change on constant entities. I argue that the idea of change, that is, change without losing complexity or even increasing it, being based on modifications of the otherwise reliable transmission of genomes over long periods of time has a historical parallel in the writings of these ancient speculative thinkers, notwithstanding the fundamental differences between the two thought systems.

The social construction of the social epigenome and the larger biological context.

Epigenetics researchers in developmental, cell, and molecular biology greatly diverge in their understanding and definitions of epigenetics. In contrast, social epigeneticists, e.g., sociologists, scholars of STS, and behavioural scientists, share a focus and definition of epigenetics that is environmentally caused and trans-generationally inherited. This article demonstrates that this emphasis on the environment and on so-called Lamarckian inheritance, in addition to other factors, reflects an interdisciplinary power struggle with genetics, in which epigenetics appears to grant the social sciences a higher epistemic status. Social scientists' understanding of epigenetics, thus, appears in part to be socially constructed, i.e., the result of extra-scientific factors, such as social processes and the self-interest of the discipline. This article argues that social epigeneticists make far-reaching claims by selecting elements from research labelled epigenetics in biology while ignoring widely confirmed scientific facts in genetics and cell biology, such as the dependence of epigenetic marks on DNA sequence-specific events, or the lack of evidence for the lasting influence of the environment on epigenetic marks or the epigenome. Moreover, they treat as a given crucial questions that are far from resolved, such as what role, if any, DNA methylation plays in the complex biochemical system of regulating gene activity. The article also points out incorrect perceptions and media hypes among biological epigeneticists and calls attention to an apparent bias among scientific journals that prefer papers that promote transgenerational epigenetic inheritance over articles that critique it. The article concludes that while research labelled epigenetics contributes significantly to our knowledge about chromatin and the genome, it does not, as is often claimed, rehabilitate Lamarck or overthrow the fundamental biological principles of gene regulation, which are based on specific regulatory sequences of the genome.

From Gregor Mendel to Eric Davidson: Mathematical Models and Basic Principles in Biology.

Mathematical models have been widespread in biology since its emergence as a modern experimental science in the 19th century. Focusing on models in developmental biology and heredity, this article (1) presents the properties and epistemological basis of pertinent mathematical models in biology from Mendel's model of heredity in the 19th century to Eric Davidson's model of developmental gene regulatory networks in the 21st; (2) shows that the models differ not only in their epistemologies but also in regard to explicitly or implicitly taking into account basic biological principles, in particular those of biological specificity (that became, in part, replaced by genetic information) and genetic causality. The article claims that models disregarding these principles did not impact the direction of biological research in a lasting way, although some of them, such as D'Arcy Thompson's models of biological form, were widely read and admired and others, such as Turing's models of development, stimulated research in other fields. Moreover, it suggests that successful models were not purely mathematical descriptions or simulations of biological phenomena but were based on inductive, as well as hypothetico-deductive, methodology. The recent availability of large amounts of sequencing data and new computational methodology tremendously facilitates system approaches and pattern recognition in many fields of research. Although these new technologies have given rise to claims that correlation is replacing experimentation and causal analysis, the article argues that the inductive and hypothetico-deductive experimental methodologies have remained fundamentally important as long as causal-mechanistic explanations of complex systems are pursued.

Introduction: Eric Davidson and the molecular biology of evolution and development.

Between November 30th and December 2nd, 2015, the Jacques Loeb Centre for the History and Philosophy of the Life Sciences at Ben-Gurion University of the Negev in Beer Sheva (Israel) held its Eighth International Workshop under the title "From Genome to Gene: Causality, Synthesis and Evolution". Eric Davidson, the founder of the concept of developmental Gene Regulatory Networks, had regularly attended the previous meetings, and his participation in this one was expected, but he suddenly passed away 3 months before. In this paper, we provide an introduction and overview on five papers that were presented at the workshop and examine the importance of genomes and gene regulatory networks in extant biology, developmental biology, evolutionary biology and medicine, as well as a collection of remembrances of Eric Davidson, of his personality as well as of his scientific contributions. Historical perspectives are provided, and the ethical issues raised by the new tools developed to modify the genome are also discussed.

Eric Davidson, his philosophy, and the history of science.

Eric Davidson, a passionate molecular developmental biologist and intellectual, believed that conceptual advances in the sciences should be based on knowledge of conceptual history. Convinced of the superiority of a causal-analytical approach over other methods, he succeeded in successfully applying this approach to the complex feature of organismal development by introducing the far-reaching concept of developmental Gene Regulatory Networks. This essay reviews Davidson's philosophy, his support for the history of science, and some aspects of his scientific personality.

Hierarchy, determinism, and specificity in theories of development and evolution.

The concepts of hierarchical organization, genetic determinism and biological specificity (for example of species, biologically relevant macromolecules, or genes) have played a crucial role in biology as a modern experimental science since its beginnings in the nineteenth century. The idea of genetic information (specificity) and genetic determination was at the basis of molecular biology that developed in the 1940s with macromolecules, viruses and prokaryotes as major objects of research often labelled "reductionist". However, the concepts have been marginalized or rejected in some of the research that in the late 1960s began to focus additionally on the molecularization of complex biological structures and functions using systems approaches. This paper challenges the view that 'molecular reductionism' has been successfully replaced by holism and a focus on the collective behaviour of cellular entities. It argues instead that there are more fertile replacements for molecular 'reductionism', in which genomics, embryology, biochemistry, and computer science intertwine and result in research that is as exact and causally predictive as earlier molecular biology.

Epigenetics: The origins and evolution of a fashionable topic.

The term "epigenetics" was introduced in 1942 by embryologist Conrad Waddington, who, relating it to the 17th century concept of "epigenesis", defined it as the complex of developmental processes between the genotype and phenotype. While in the years that followed, these processes - in particular gene regulation - were tackled, not in the frame of epigenetics but of genetics, research labelled "epigenetics" rose strongly only in the 21st century. Then it consisted of research on chromatin modifications, i.e. chemical modifications of DNA or histone proteins around DNA that do not change the base sequence. This rise was accompanied by far-reaching claims, such as that epigenetics provides a mechanism for "Lamarckian" inheritance. This article highlights the origin of epigenetics, the major phases of epigenetic research, and the changes in the meaning of the term. It also calls into question some of the far-reaching claims that have accompanied the recent rise of epigenetics.

Chromatin: Its history, current research, and the seminal researchers and their philosophy.

The concept of chromatin as a complex of nucleic acid and proteins in the cell nucleus was developed by cytologists and biochemists in the late 19th century. It was the starting point for biochemical research on DNA and nuclear proteins. Although interest in chromatin declined rapidly at the beginning of the 20th century, a few decades later a new focus on chromatin emerged, which was not only related to its structure, but also to its function in gene regulatory processes in the development of higher organisms. Since the late 20th century, research on chromatin modifications has also been conducted under the label of epigenetics. This article highlights the major phases of chromatin research until the present time and introduces major investigators and their scientific and philosophical outlooks.

The concept of the causal role of chromosomes and genes in heredity and development: opponents from Darwin to Lysenko.

The idea of chromosomes and genes as causal agents in development and heredity originated in late 19th-century cytology, and it was most strongly supported by Theodor Boveri and Edmund B. Wilson. The concept of genes, which was central and most fruitful in classical genetics, appeared, however, unappealing and insufficient to many for explaining complex biological phenomena such as development.Philosophical outlooks, among them "Lamarckian" and holistic predilections, played a significant role in scientists' objection to genes as causal factors. A wide conceptual gap between genetics and developmental biology ensued. The strongest attack on the concept of genes was launched by agronomist and politician Trofim Lysenko in the Soviet Union under Stalin. Brushing aside the "Mendelist-Morganist" methods of classical genetics, Lysenko put forward a holistic concept of heredity that incorporated development and heritable responses to environmental conditions, similar to Darwin's Pangenesis theory, though of course some 60 years later. Recent developments include the role of genes in research on epigenetic marks and in systems approaches based on embryological gene regulatory networks.

Commemorating the 1913 Michaelis-Menten paper Die Kinetik der Invertinwirkung: three perspectives.

Methods and equations for analysing the kinetics of enzyme-catalysed reactions were developed at the beginning of the 20th century in two centres in particular; in Paris, by Victor Henri, and, in Berlin, by Leonor Michaelis and Maud Menten. Henri made a detailed analysis of the work in this area that had preceded him, and arrived at a correct equation for the initial rate of reaction. However, his approach was open to the important objection that he took no account of the hydrogen-ion concentration (a subject largely undeveloped in his time). In addition, although he wrote down an expression for the initial rate of reaction and described the hyperbolic form of its dependence on the substrate concentration, he did not appreciate the great advantages that would come from analysis in terms of initial rates rather than time courses. Michaelis and Menten not only placed Henri's analysis on a firm experimental foundation, but also defined the experimental protocol that remains standard today. Here, we review this development, and discuss other scientific contributions of these individuals. The three parts have different authors, as indicated, and do not necessarily agree on all details, in particular about the relative importance of the contributions of Michaelis and Menten on the one hand and of Henri on the other. Rather than force the review into an unrealistic consensus, we consider it appropriate to leave the disagreements visible.

Crystals, colloids, or molecules?: Early controversies about the origin of life and synthetic life.

Crystals, colloids, and (macro-)molecules have played major roles in theoretical concepts and experimental approaches concerning the generation of life from the mid-19th century on. The notion of the crystallization of life out of a nonliving fluid, a special case of the doctrine of spontaneous generation, was most prominently incorporated into Schleiden's and Schwann's version of cell theory. Refutation at the end of the 19th century of spontaneous generation of life and cells, in particular by Pasteur, Remak, and Virchow, not only gave rise to the flourishing fields of microbiology and cytology, but it also opened up research on synthetic life. These approaches focused on growth and form and colloidal chemistry on the one hand, and on the specificity of organisms' macromolecules and chemical reactions on the other. This article analyzes the contribution of these approaches to synthetic life research and argues that researchers' philosophical predilections and basic beliefs have played important roles in the choice of experimental and theoretical approaches towards synthetic life.

Beyond Popper and Polanyi: Leonor Michaelis, a critical and passionate pioneer of research at the interface of medicine, enzymology, and physical chemistry.

The biochemist and biophysicist Leonor Michaelis (1875-1949) was a renowned pioneer who worked at the interface of physical chemistry and biochemistry. He is best known for his work on the physical chemistry of proteins and enzymes and for the mathematical derivation, together with Maud Menten, of the affinity constant of the enzyme substrate bond, now known as the Michaelis-Menten constant. His thorough experimentation and careful theorizing made him critical of his contemporaries in medical biochemistry, whose work did not withstand scrutiny. His strong influence resulted from combining new concepts and approaches with traditional ones, thus bridging conceptual gaps. Most importantly, his success was brought about because he combined a critical and sharp mind with competence, passion, and determination. A review of Michaelis's approach and achievements shows that critical theory testing, as suggested by Popper, cannot explain scientific advance if taken alone; the existence of a passionate commitment to scientific beliefs, as emphasized by Polanyi, is another necessary prerequisite for the development of science.